OP0200 ORAL DELIVERY OF DELTA-9-TETRAHYDROCANNABINOL PROVIDES SYMPTOM AND DISEASE MODIFICATION USING TWO MODELS OF KNEE OSTEOARTHRITIS
Authors: J. Rockel, A. Maglaviceanu, H. Fetter Filippini, E. Poduch, M. Lewis-Bakker, J. Garcia, T. Leroux, H. Clarke, R. Bonin, L. Kotra, M. Kapoor
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is a whole joint disease that results in joint pain, cartilage degeneration, and synovitis, ultimately reducing the quality of life of those affected. Current therapies only modify pain and there are no approved OA disease-modifying drugs. Recent studies suggest that individuals with OA are self-medicating with cannabis, with some anecdotally reporting reduced joint pain. One of the most prominent cannabinoids in cannabis is delta-9-tetrahydrocannabinolic acid, which produces the psychoactive compound delta-9-tetrahydrocannabinol (THC) upon decarboxylation. THC can signal via CB1 and CB2 cannabinoid receptors to alter intracellular cAMP levels. CB1 and CB2 are found on joint cells, including chondrocytes and fibroblast-like synoviocytes (FLS). Currently, there are no studies linking THC to disease modification in OA. <h3>Objectives</h3> In this study, we investigated the effects and mechanisms of action of THC on pain and disease modification in pre-clinical models of knee OA. <h3>Methods</h3> 14-16 week (wk)-old male C57BL/6 mice underwent sham or destabilization of the medial meniscus (DMM) surgery to induce knee OA. At 1 wk post-surgery, THC (1, 5 or 10 mg/kg) or vehicle was administered 1 day/wk by intra-articular (IA) injection, or 5 days/wk by oral gavage for 9 wks. Von Frey and Open Field testing were performed to evaluate mechanical allodynia and locomotion/anxiety. 10 wks post-surgery joints were subjected to histopathology. For the monosodium iodoacetate (MIA) model of OA pain, knees of 14-wk-old C57BL/6 mice were injected with saline (control) or MIA (0.5 mg) and mice were administered THC (5 or 10mg/kg) 5 days/wk by oral gavage for 3 wks and Von Frey analyses was performed to evaluate mechanical allodynia. For in vitro studies, human FLS and chondrocytes obtained from OA patients undergoing total knee arthroplasty were subjected to flow cytometry and RNA sequencing with/without THC treatment. <h3>Results</h3> IA administration of THC to DMM mice accelerated cartilage degeneration, increased synovitis, and failed to attenuate mechanical allodynia at all doses (n=5/group). Oral administration of THC at all doses reduced cartilage degeneration, with only 10 mg/kg THC also reducing synovitis (n=10-15/group; Figure 1A&amp;B). IHC of DMM joints (n=6/group) suggested significantly decreased αSMA but not nuclear Ki67 expression in the synovial subintima with THC oral gavage administration. Von Frey tests showed that administration of THC by oral gavage reduced mechanical allodynia in DMM mice at 9 wks post-surgery (n=15/group; Figure 1C). Open field tests indicated that THC had no overt effect on the locomotion or anxiety of sham or DMM mice (n=10/group). Studies using MIA-induced OA mice showed that administration of 10 mg/kg THC by oral gavage also reduced mechanical allodynia (n=10/group) without modifying animal locomotion or anxiety. In vitro, THC treatment of human OA FLS and chondrocytes (n=5 each) increased Annexin V positivity starting at 2.5µM, but not with 1µM THC, as determined by flow cytometry. In cultured OA FLS (n=4), 73 genes were differentially expressed (35 upregulated, 38 downregulated) after treatment with THC compared to vehicle treatment (≥1.5-fold), as determined by RNA sequencing (Figure 1D). Similarly, in OA chondrocytes RNA sequencing (n=4/group), 21 genes (9 upregulated, 12 downregulated) were differentially expressed (≥1.5-fold) after THC treatment. Computational analyses indicated that ECM-related pathways were enriched in the upregulated genes in both fibroblasts and chondrocytes, while lipid/steroid/cholesterol-related pathways were enriched by the downregulated genes in both cell types. 22 common putative transcription factors were also identified as potential regulators of the fibroblast and chondrocyte genes reduced through THC treatment. <h3>Conclusion</h3> Oral administration of 10 mg/kg THC reduced cartilage degeneration and synovitis in DMM mouse knee joints and modified pain responses in DMM and MIA models. JR, AM, HFF share equal first author contribution. <h3>Acknowledgements</h3> Canadian Institute of Health Research and The Arthritis Society of Canada. <h3>Disclosure of Interests</h3> None Declared.